Designing induction therapies to target memory T cells in high risk recipients

描述（由申请人提供）：同种异体反应性记忆T细胞在临床移植中存在严重障碍。抗体介导的耗竭被广泛用作致敏移植受者的诱导治疗，以克服预先存在的供体反应性免疫的有害影响。然而，记忆T细胞是不太容易耗尽比na？ve T细胞，目前还没有努力提高诱导疗法在靶向预先存在的供体反应性T细胞记忆中的功效。我们先前在使用兔抗鼠胸腺球蛋白（mATG）的小鼠心脏移植模型中的研究表明，记忆T细胞是淋巴消融后抗供体免疫应答的主要组分，并且恢复记忆CD 8 T细胞是mATG治疗的受体中介导同种异体移植物排斥的主要效应机制。初步实验确定了两组信号驱动抗体介导的耗竭后记忆CD 8 T细胞的恢复：通过B细胞介导的CD 4 T细胞的帮助和移植后炎症。这项研究的目的是确定抗体介导的耗竭后记忆T细胞重建的机制，并利用这些信息制定抑制记忆T细胞恢复和改善高危受者同种异体移植结局的策略。我们假设1）干扰辅助和促炎信号将有效抑制记忆性CD 8 T细胞恢复并增加Treg/Teff细胞比率以阻止致病性抗供体应答的发展，和2）这些临床上可行的策略将改善含有同种异体反应性记忆T细胞的高风险接受者中淋巴细胞耗竭诱导疗法的功效，缺血时间我们将在三个具体目标中检验这一假设：目标1。确定抗体介导的淋巴消融后记忆T细胞重建的细胞和分子要求。目标2.测试移植后炎症对ATG治疗的受者中记忆T细胞恢复和功能的影响。目标3。通过淋巴清除策略检测调节性T细胞对移植物延长的贡献。我们预计，这些研究中开发的方法将专门针对预先存在的供体反应性记忆T细胞，并将提高致敏移植患者淋巴消融术的疗效。

DESCRIPTION (provided by applicant): Alloreactive memory T cells present a serious hurdle in clinical transplantation. Antibody-mediated depletion is widely used as induction therapy in sensitized transplant recipients to overcome the deleterious effects of preexisting donor-reactive immunity. However, memory T cells are less susceptible to depletion than na?ve T cells and there are no current efforts to improve the efficacy of induction therapies in targeting pre-existing donor-reactive T cell memory. Our previous studies in a mouse model of cardiac transplantation using rabbit anti-murine thymoglobulin (mATG) showed that memory T cells are a dominant component of anti-donor immune responses following lymphoablation and that recovering memory CD8 T cells are the primary effector mechanism mediating allograft rejection in mATG treated recipients. Preliminary experiments identified two groups of signals driving memory CD8 T cell recovery following antibody-mediated depletion: help from CD4 T cells mediated through B cells and post-transplant inflammation. The goal of the proposed study is to determine the mechanisms of memory T cell reconstitution following antibody mediated depletion and to use this information to develop strategies inhibiting memory T cell recovery and improving allograft outcome in high risk recipients. We hypothesize that 1) interference with helper and pro-inflammatory signals will effectively inhibit memory CD8 T cell recovery and increase the Treg/Teff cell ratio to impede the development of pathogenic anti-donor responses, and 2) these clinically feasible strategies will improve the efficacy of lymphocyte depleting induction therapies in high risk recipients containing alloreactive memory T cells and receiving cadaveric donor organs with prolonged ischemia time. We will test this hypothesis in three Specific Aims: Aim 1. To determine cellular and molecular requirements for memory T cell reconstitution following antibody - mediated lymphoablation. Aim 2. To test the effects of post-transplant inflammation on memory T cell recovery and functions in ATG treated recipients. Aim 3. To test the contribution of regulatory T cells to allograft prolongation by lymphoablative strategies. We anticipate that the approaches developed in these studies will specifically target pre-existing donor-reactive memory T cells and will improve the efficacy of lymphoablation in sensitized transplant patients.